Abstract: Transcranial laser stimulation (TLS) involves using low-power, high-fluence light (620?1100 nm) to regulate neuronal functions. The mechanism of TLS relies on photon absorption by cytochrome c oxidase (CCO). Photoactivation of this terminal enzyme in the mitochondrial respiratory chain plays a key role in cerebral oxygen utilization for energy metabolism. This photonics-bioenergetics mechanism results increased cerebral metabolism that appears to benefit for cognitive enhancement and neuroprotection. In recent years, TLS has shown therapeutic potential for treating a number of neurological and psychological disorders. However, uncertainty remains about the mechanism of action of TLS in the human brain in vivo. There is a lack of evidence of whether or not changes in neuronal functions are associated with changes in cerebral metabolism induced by TLS. Furthermore, there is not a feasible means to measure the cerebral metabolic changes during TLS. Being able to simultaneously deliver TLS and record the cerebral metabolic changes in vivo would be a significant essential step toward making TLS a viable treatment option. The propose research aims to develop a non-invasive and cost-effective optical imaging approach to quantify and better understand the in vivo cerebral metabolic effects of TLS and, importantly, to assess whether these effects correlate with participants? improvements in cognitive functions. We will build a hybrid system of broadband near-infrared spectroscopy (NIRS) and diffuse correlation spectroscopy (DCS) to quantify relative changes of CCO and cerebral metabolic rate of oxygen (rCMRO2) in the human brain in vivo. Then, we will conduct the first placebo-controlled human study to identify the primary cerebral metabolic effects of TLS (i.e., changes in CCO and rCMRO2), by comparing the results against those from a placebo-treated control group. We will further conduct two sessions of cognitive tests, one before the TLS or placebo stimulation and another immediately following the stimulation, to identify the participants? potential changes in cognitive performance due to TLS. This will allow us to assess whether there is a significant relationship between the cerebral metabolic changes and changes in cognitive performance in the TLS-treated participants. To complete the research aims outlined above, we have formed a strong and multidisciplinary team with exceptional research acumen in their fields. The success of this study will provide much needed insight into the underlying mechanism of TLS-generated metabolic activity in the human brain in vivo. Furthermore, it will demonstrate the feasibility of a non-invasive and cost-effective treatment-with-imaging approach. This novel therapeutic approach could optimize treatment for individuals who have suffered cognitive impairments resulting from a number of neurological and psychological disorders.